The optic nerve is made up of approximately 1 to 1.5 million nerve fibers or axons along with supporting glial cells and blood vessels (Anderson, D. (2004) “The Optic Nerve Head in Glaucoma” Duane's Ophthalmology). The optic nerve head (ONH) is the exit in the outer retina where all the nerve fibers pass through the chorioscleral canal or neural canal opening on their path to the brain. As shown in FIG. 1, the nerve fibers i.e. 102 are shown in the figure as striations distributed across the entire retina in the nerve fiber layer (NFL) or retinal nerve fiber layer (RNFL), and converge at the ONH 101. At this point, the nerve fiber bundles are at their most concentrated, forming what is known as the neuroretinal rim 103. The neuroretinal rim is a 3D structure bounded by the optic disc margin on the outside and the optic cup margin on the inside. The optic cup is a physiological excavation that results if the chorioscleral canal is larger than the optic nerve itself. As will be discussed further below, the boundary of the optic cup margin is open to interpretation and such vagueness has hindered the clinical utility of measurements of the neuroretinal rim.
Different optic neuropathies manifest themselves as atrophying of nerve fibers. In glaucoma, for example, the NFL thins as a direct result of ganglion cell apoptosis (the retinal neurons responsible for transmitting visual information) which leads to nerve fiber loss. In other types of optic neuropathies the NFL will also typically thin as a general result of nerve fiber injury (Frohman E et al. (2008). “Optical Coherence Tomography: A Window into the mechanisms of multiple sclerosis” Nat. Clin. Prac. Neurol. 4(12): 664-675). In theory, any nerve fiber loss will manifest itself as thinning at the neuroretinal rim as any retinal nerve fiber belongs to that particular landmark. Therefore, an objective and accurate structural measurement of the neuroretinal rim is central to disease management and diagnosis. Unique to the eye, the ganglion cell nerve fibers are unmylenated, and the ability to directly measure them creates potential diagnostics in the field of neurology.
The gold-standard structural assessment of the ONH is based on a manual estimation of the delineation of optic disc and optic cup margins performed by an expert clinician based on an ophthalmic examination with anophthalmascope and/or fundus photography (see for example U.S. Pat. No. 6,415,173). This assessment is highly subjective. Using stereo fundus photography, depth cues may be inferred to improve the estimate, but the method remains subjective, indirect, and variable (See for example Coleman A. et al. (1996). “Interobserver and intraobserver variability in the detection of glaucomatous progression of the optic disc” J. Glaucoma 5:384-9 and Tielsch J. et al. (1988) “Intraobserver and interobserver agreement in measurement of optic disc characteristics” Ophthalmology 95:350-6). Furthermore, the disc margin is often hard to see in fundus images as a result of either poor image quality or because the boundary is obscured by other anatomy such as the nerve fiber bundles themselves or the vessel structure also converging in that region. The measurements are also difficult to repeat because of their subjective nature hindering their ability to accurately determine if changes in the metric are a result of disease progression or, more simply, the difference in the subjective evaluation. While efforts have been made to develop means to remove subjectivity, by allowing comparison over time, by directly superimposing two digital images (see for example U.S. Pat. No. 6,698,885), and automation to identify pixels associated with cup, rim and vessels (see for example, U.S. Pat. No. 7,712,898), the method remains largely subjective in nature.
Automated measurements of the ONH exist, but have different drawbacks. One commercial device offering such functionality is the HRT (Heidelberg Retina Tomograph, Heidelberg Engineering, Inc, Germany), which uses a 670 nm wavelength laser as its light source to build a 3D image of the surface topography of the ONH (see for example U.S. Pat. No. 7,203,351). It is a confocal system and covers approximately 2500 microns axially. Its ability to accurately image the topography of the ONH relies entirely on the user's choice of the focal plane, about which a series of 2D confocal images are acquired—spaced at around 80 microns apart—and then summed to form a representative 2D image. A 3D image is constructed based on the intensity profile across the axial range; depth is simply the profile's largest response. FIG. 2 shows a portion of the analysis report of the HRT. The image shows three regions corresponding to the optic cup and optic disc analysis. The central region 201 corresponds to the optic cup and the other two regions 202 and 203 correspond to the optic disc where 202 indicates the slope.
The HRT's ability to automatically measure ONH structure relies on a manual delineation of the optic disc margin, and then bases the optic cup margin as the intersection of the vitreoretinal interface (VRI) or inner limiting membrane (ILM) at a fixed offset from the disc's reference plane, which is automatically defined. As such, the HRT simply determines the optic cup margin as an area away from the reference plane and within the contour of the optic disc margin. This is not based on a given repeatable landmark, as might be used by the clinician, and the variability of the reference plane itself is an additional source of variation in the measurement (See Heidelberg on-line FAQ: http://www.heidelbergengineering.com/technical-support-heidelberg-engineering/faq-topics/hrt3-glaucoma-faqs/#faq—791 and Poli A. et al. (2008). “Analysis of HRT images: comparison of reference planes” Ophthalmology & Visual Science 49(9)).
The Stratus-OCT (Carl Zeiss Meditec, Inc, Dublin Calif.) with an axial resolution of approximately 10 microns, is able to find the disc margin automatically, but due to a similar definition of the optic cup margin as the HRT in terms of an offset, still suffers from robustness issues. FIG. 3 displays a two-dimensional (2D) illustration of how the optic cup margin is defined in the Stratus system. After defining the optic disc margin 303 at the endpoints of the RPE 302, the optic cup margin 305 is defined in reference to a plane parallel to the plane of the optic disc 303 at an offset 304 where it intersects the VRI 301. The choice of the offset from the plane of the disc is arbitrary and determines the size of the cup, leaving its anatomical meaning unclear. Should the user wish to best correlate the cup as then delineated by the automated software to that defined by the clinician from fundus photographs, it needs to be manually adjusted (see Savini G et al. (2009). “Agreement between optical coherence tomography and digital stereophotography in vertical cup-to-disc ratio measurement” Graefe's Arch. Clin. Exp. Ophthalmol 247(3):377-383). More importantly, the choice of offset can inadvertently affect the ability of the measurement to distinguish disease from normal structure (see Leung C. et al (2005). “Analysis of Retinal nerve fiber layer and optic nerve head in glaucoma with different reference plane offsets using optical coherence tomography” Invest Ophthalmol and Vis Sci 46:891-899).
This definition of the cup in terms of an offset has continued with some newer Spectral Domain OCT (SD-OCT) devices. FIG. 4 shows a cross-sectional schematic illustrating the definition of cup and disc as available in the commercial software (version 4.0) of the RTVue instrument (Optovue Inc., Fremont, Calif.). The optic disc 401 is defined as the termination of the RPE 402. This defines the disc's plane. The optic cup 403 is defined to be where a plane at an offset of 150 microns above that plane (a line in the 2d cross section above) intersects the VRI 404. Based on these definitions, measurements relating to the neuroretinal rim including the rim volume (shown in cross-sectional view) 405 and the nerve head volume (shown in cross-sectional view) 406 are derived.
In light of the above there is a need for an automated, repeatable and accurate method of analyzing the ONH that provides anatomically relevant and unambiguous definitions of the optic disc and optic cup margins to make and display clinically meaningful measurements.